Variant rs80338684 details in Genebe, Genetics Data Aggregator

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 22 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 117 pathogenic variants in the truncated region.

PS1

Transcript NM_001370658.1 (BTD) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 3-15635477-GCGGCTG-TCC is Pathogenic according to our data. Variant chr3-15635477-GCGGCTG-TCC is described in ClinVar as [Pathogenic]. Clinvar id is 1895.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BTD	NM_001370658.1 link	c.38_44delGCGGCTGinsTCC	p.Cys13fs	frameshift_variant, missense_variant	2/4	ENST00000643237.3	NP_001357587.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BTD	ENST00000643237.3 link	c.38_44delGCGGCTGinsTCC	p.Cys13fs	frameshift_variant, missense_variant	2/4		NM_001370658.1	ENSP00000495254.2		P43251-4

Frequencies

GnomAD3 genomes

Cov.:

32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

Cov.:

32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:18Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Biotinidase deficiency

Pathogenic:15Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 1996	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 24, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jun 23, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics Lab, CHRU Brest	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 20, 2019	NM_000060.2(BTD):c.98_104del7ins3(C33Ffs36) is classified as pathogenic in the context of biotinidase deficiency. Sources cited for classification include the following: PMID 7550325. Classification of NM_000060.2(BTD):c.98_104del7ins3(C33Ffs36) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening. -
Pathogenic, criteria provided, single submitter	research	Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	Oct 04, 2024	PVS1,PM3,PM2 -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 15, 2023	The p.Cys13PhefsX36 (c.38_44delinsTCC) variant in BTD has been reported in >10 homozygous and > 10 compound heterozygous individuals with biotinidase deficiency and segregated with disease in 1 affected homozygous relative from 1 consanguineous family (Pomponio 1995 PMID: 7550325, Senanayake 2015 PMID: 28649532, Asgari 2016 PMID: 27845546, Wolf 2017 PMID: 27657684, Ferreira 2017 PMID: 28220409, Al-Eitan 2020 PMID: 31973013). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 1895) and has also been identified in as two separate variants (40_41delGG and c.44_45delGT) in gnomAD in 0.08% (4/4836) South Asian and 0.02% (15/68040) European chromosomes (http://gnomad.broadinstitute.org v.3.1.2). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 13 and leads to a premature termination codon 36 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the BTD gene is an established disease mechanism in autosomal recessive biotinidase deficiency. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive biotinidase deficiency. ACMG/AMP Criteria applied: PVS1, PM3_Very Strong. -
Pathogenic, criteria provided, single submitter	clinical testing	Centogene AG - the Rare Disease Company	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 26, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 25, 2015	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 26, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 27, 2022	This sequence change creates a premature translational stop signal (p.Cys33Phefs*36) in the BTD gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BTD are known to be pathogenic (PMID: 20083419). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with biotinidase deficiency (PMID: 7550325, 27657684, 27845546, 28220409; Invitae). ClinVar contains an entry for this variant (Variation ID: 631911). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Suma Genomics	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The frameshift variant c.38_44delGCGGCTGinsTCC (p.Cys13PhefsTer36) in the BTD gene has been reported as homozygous/compound heterozygous state in individuals affected with biotinidase deficiency (Canda et al., 2018; Al-Eitan et al., 2020). Experimental studies have shown that this frameshift variation affects protein function (Mardhiah et al., 2019). The variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. It is submitted to ClinVar as Pathogenic. This variant is predicted to cause a loss of normal protein function through protein truncation. Loss of function variants has been previously reported to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 26, 2021	The BTD c.98_104delinsTCC; p.Cys33PhefsTer36 variant (rs80338684) is reported in the literature in the homozygous or compound heterozygous state in multiple individuals affected with profound biotinidase deficiency (Pomponio 1995, Senanayake 2015, Ferreira 2017, Al-Eitan 2020, GeneReviews) and is also reported as pathogenic in ClinVar (Variation ID: 1895). This variant is observed on 36 alleles in the Genome Aggregation Database, with an allele frequency of 0.059% (18/30610 alleles) in the South Asian population. This variant causes a frameshift by deleting seven and inserting three nucleotides, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Pomponio RJ et al. Mutational hotspot in the human biotinidase gene causes profound biotinidase deficiency. Nat Genet. 1995 Sep;11(1):96-8. PMID: 7550325. Senanayake DN et al. First contiguous gene deletion causing biotinidase deficiency: The enzyme deficiency in three Sri Lankan children. Mol Genet Metab Rep. 2015 Feb 7;2:81-84. PMID: 28649532. Ferreira P, Chan A, Wolf B. Irreversibility of Symptoms with Biotin Therapy in an Adult with Profound Biotinidase Deficiency. JIMD Rep. 2017;36:117-120. PMID: 28220409. Al-Eitan LN et al. Identification and Characterization of BTD Gene Mutations in Jordanian Children with Biotinidase Deficiency. J Pers Med. 2020 Jan 21;10(1):4. PMID: 31973013. Wolf B et al. Biotinidase Deficiency. 2000 Mar 24 [updated 2016 Jun 9]. GeneReviews. PMID: 20301497. https://www.ncbi.nlm.nih.gov/books/NBK1322/ -

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 14, 2021	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 15776412, 22975760, 22011816, 31973013, 27845546, 26361991, 7550325, 28281033, 27657684, 28220409, 20083419, 28649532, 34302356, 33364171, 33083013, 32235217) -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Nov 03, 2023	The BTD c.98_104delinsTCC (p.Cys33Phefs*36) variant alters the translational reading frame of the BTD mRNA and causes the premature termination of BTD protein synthesis. This variant has been reported in the published literature in individuals with biotinidase deficiency (PMIDs: 9099842 (1997), 15776412 (2005), 20083419 (2010), 27845546 (2016), 27329734 (2016), 28220409 (2017), 27657684 (2017)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 31, 2014	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

rs80338684

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation